Introduction

Prostatic cancer is among the frequent cancers in the world after the skin cancer in terms new cancer cases and annual causalities.¹ About 0.3 million new cases has been registered in 2024,. The data for the onset of prostrate cancer (PC) varies in the developed and under developing countries.² Key risk factors of the PC are gender and aging associated as indicated by the statistics are reported in men and during mid 60s.³ Family history, race which is AA males and brca1/brca2 mutations all are the related primary risk factors but these remained a syptomatic during early years.⁴ Thus, PC and its progression is a complex phenomenon that comprised of genotypes, environment and hormonal dysregulation. This gradually progress from prostatic intraepithelial neoplasia (PIN) and localized adenocarcinoma that metastasize to other organs. Underlying mechanism for carcinogenesis is based on an alteration in signal transduction of androgen receptors, loss of PTEN tumor suppressor gene and even gain of multiple copies of MYC and related genes. Several epigenetic modes imply DNA methylation and histones in carcinogenesis and malignant transformation have been proposed.⁵

Treatment of PC depends on the stage of cancer and resources such as active surveillance or surgery followed by radiation and hormonal agents such as ADT, chemotherapy, immunotherapy or enzyme inhibitors PARP.⁶ PARP inhibitors and immunotherapies are thought as novel and still demand investigations to improve treatment efficacy and outcomes. Understanding epidemiology, risk factors, pathogenesis, and molecular mechanisms of PC, is crucial for developing effective prevention strategies and superior treatment options. Ongoing research of personalized medicine and precision oncology holds promise for improving outcomes and quality of life for PC patients.⁷

Chemotherapies are effective methods of cancer control especially in the high-risk populations. Chemopreventive molecules prevent cancer in early stages of carcinogenesis, later on complications, and mortalities. Mechanistically, these drug molecules follow diverse cellular pathways, modulate carcinogenesis and upregulate detoxification enzymes at translational level. Moreover, these drug molecules act as strong antioxidants that neutralize DNA damaging reactive oxygen species (ROS), alters fundamental cell signaling involving nuclear factor kappa B (NF-κB) and PI3K/Akt pathway essential for cell proliferation and survival, and prevent COX-2 expression.⁸ In addition, these natural bioactive drug molecules promote apoptosis in precancerous or cancerous cells without affecting normal cells.⁹ Recent research highlights the effectiveness of specific substances in maintaining the malaise from PC.⁹ For instance, finasteride (25% reduction) and dutasteride (23% reduction) have shown notable decrease in PC development in the patients as indicated by prostrate cancer prevention trial (PCPT) studies.¹⁰

Tea plant (Camellia sinensis) native to East-Asia and Southeast-Asia much valued for its leaves that are processed into different types of tea.¹¹ Green tea, made from unoxidized leaves, which keeps its light flavor and contains bioactive molecules i.e., catechins, which are beneficial for health by posing antioxidant and anti-inflammatory effects. Black tea is also brewed from C. Sinensis leaves is fully oxidized boasting of rich flavors comprised of theaflavins and thearubigins which have metabolic and cardiovascular health benefits. Oolong tea is partially oxidized, exhibits complex flavors and is noted for its potential in weight management and regulating metabolic activities.¹² White tea is one of the least processed form of young leaves and possess low flavor profile bearing potentially more antioxidants. Moreover, tea EGCG probably has the potential to influence carcinogenic activity. Tea polyphenols including EGCG show antioxidant activities and altered signal transduction pathways having potential roles in carcinogenesis.¹³

Tea holds significant historical and cultural importance, evolving from its origins as a medicinal beverage in ancient times to becoming a globally beloved drink.¹⁴ Tea antioxidants have various benefits including promotion of cardiovascular health, enhancement of attention span and memory, prevention of chronic ailments, reducing inflammation, and overall body immunity. More and more studies are exploring the diverse health benefits of tea and its potential use in modern day life to prevent life style oriented ailments, significance in global health and wellness.¹⁵

BACs in C. sinensis

Studies confirmed the presence of different polyphenols in tea plant which have string pharmacological potential. C. sinensis is rich in antioxidant catechins which further classified into epigallocatechingallate (EGCG), epigallocatechin (EGC), epicatechingallate (ECG), and epicatechin (EC). EGCG, in particular, has garnered attention for its potential health benefits, including anti-cancer, anti-inflammatory, and cardioprotective effects.¹² Regarding flavonoids, C. sinensis contains quercetin, kaempferol, and myricetin, which contribute to its antioxidant activity and potential health benefits.¹⁶ There exists numerous differences in purine alkaloids and are thought as quality components in tea. C. sinensis naturally contains caffeine, a stimulant that can enhance alertness and concentration. Caffeine contents varies among different tea types, with higher concentrations in black tea compared to green and white teas.¹⁷ Another alkaloid theobromine, found in cocoa and chocolate may contributes to stimulating effects.¹⁸ Presence of theanine moderate the stimulating effects of caffeine, contributing to reputation of  tea as a calming beverage worldwide.¹⁹

C. sinensis is rich in vitamins and minerals, and their concentration depends on tea type and brewing methods. Commonly vitamin C, E, and B-complex, various minerals like Mn, K, and F are also present.¹⁹ Tea leaves also contain certain volatile oils including terpenes, sesquiterpenes, and other aromatic compounds, which contribute to their aroma and flavor profiles (Figure 1).²⁰

Mechanism of action of C. sinensis BACs

BACs in C. sinensis represent a broad category of compounds that contribute to its health-promoting properties.²¹ Of these compounds, catechins are notable, and flavonoids are known for their higher antioxidant potential. Catechins like EGCG is important for its beneficial effects on the human body including anticancer, anti-inflammatory, and cardiovascular disease prevention effects.²² Tea flavonoids viz. quercetin, kaempferol and myricetin add strength to the antioxidant properties and potentially bring other benefits to the consumer.²³ Alkaloids on the other hand, include caffeine and theobromine which are well-known stimulant to boost central nervous system are present in higher quantity in black tea.²⁴

Tea theanine could also decrease the alertness caused by caffeine to help promote the relaxing image of tea consumption. Tea type and brewing process may determine the quantity of different vitamins and minerals.²⁴ Minerals additives through volatile oils present in tea leaves such as terpenes and sesquiterpenes found to further enhance aroma and taste.²⁵ By these diverse BACs, in addition to the pleasant taste of the drink, tea can provide beneficial health effects that researchers continue investigating since decades.²⁶ Some important tea BACs along with their mechanism of action tabulated in table 1.

Figure 1: The chemical structures of BACs in tea (C. sinensis).  Click here to view Figure

Table 1: BACs in C. sinensis and their mechanism of action.

Mechanisms of Action in Chemoprevention

Antioxidant Activity and Redox Homeostasis

Free radicals are usually very unstable and always tries for stability by complexing with DNA, proteins or lipids.⁵² ROS produced during cellular metabolism, radiations, pollution and chemicals may cause damage to biomolecules specifically shear DNA to induce genetic mutations that lead carcinogenesis.⁵³ Polyphenolic chemopreventive agents in C. sinensis such as antioxidant EGCG donate electrons to stabilize free radicals and help avoid cellular damages. It plays a significant role in protection from oxidative damage, maintain genomic stability against mutations and caners.⁵⁴ Polyphenols can up regulate the endogenous antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase by quickly reducing ROS to less toxic or stable compounds to lower oxidative stress and its associated pathologies.⁵⁵ Some antioxidants quickly help activate generation of ROS such by NADPH oxidase and xanthine oxidase enzymes. Many polyphenols are capable to interact with such prooxidant metal ions such as free cellular iron and copper which are used as catalysts in the Fenton reaction and amplify formation of ROS.

Inhibition of NF-κB Pathway

C. sinensis chemopreventive polyphenols potently inhibit inflammatory NF-κB pathway to modulate immune responses through various mechanisms.⁵⁶ Normally, NF-κB remain inactive in the cytoplasm by binding to its inhibitor IκB,⁵⁷ and pro-inflammatory cytokines, pathogens or certain stresses activates phosphorylation of the later to release and translocate former into the nucleus.⁵⁷ Once it gets inside the nucleus, NF-κB triggers transcriptional activity for the upregulation of inflammatory cytokines, cell proliferation, supports tumor development, enlargement and metastasizing.⁵⁷ Tea polyphenolic compounds modulate NF-κB pathway through multiple signaling pathways. EGCG inhibit phosphorylation and subsequent degradation of IκB, preventing the release and nuclear translocation of NF-κB.⁵⁸ Certain phytochemicals can directly inhibit the DNA-binding activity of NF-κB, preventing it from activating its target genes.⁵⁹ By inhibiting the NF-κB pathway, these BACs could potentially reduce chronic inflammations, inhibit the proliferation and survival of cancer cells.

Activation of AMP-activated Protein Kinase (AMPK)

AMPK is prescribed as one of the molecular targets that have vital implementation for cellular energy regulation via glucose uptake, fatty acid oxidation, and mitochondrial biogenesis.²¹ Concerning cancer, it is revealed that there are more functions of AMPK associated with the cell metabolism, high glycolysis, lipogenesis, and cell growth.⁶⁰ One another signaling pathway involved in the growth of cells and synthesis of proteins is mammalian target of rapamycinm (mTOR) which is counteracted by AMPK activation.⁶⁰ The modulation of AMPK regulated metabolism is necessary for the provisions of energy rich ATPs essential for viable and enhanced growth of cancer cells. C. sinensis BACs up-regulates the level of autophagy that is a process of selective degradation of damaged cellular organelles and proteins.⁶¹ EGCG in the tea have been illustrated to regulate activation of AMPK pathway that may inhibit tumorigenesis, induce cell apoptosis, and thus considered as anticancer target and prevention strategy.⁶² Necrosis, a form of apoptosis, is essential in helping to control and shape the life of organisms since it removes damaged or abnormal cells. Mitochondrial cytochrome c happens to interact with Apaf-1 and pro-caspase-9 to form the apoptosome complex which in turns activates caspase-9, which further activates chain caspases to activate cell apoptosis through cleavage of various cellular substrates. Thus, chemopreventive agents including polyphenols from tea can activate caspases that directly leads to the selective killing of precancerous and cancerous cells to halt the further development of cancer.

Mitochondrial Pathways

The mitochondrial (intrinsic) pathway of apoptosis is regulated by Bcl-2 protein family that consists of the pro-apoptotic proteins (Bax, Bak) and anti-apoptotic proteins (Bcl-2, Bcl-xL etc.). Overall, the equilibrium between these proteins defines the cell’s destiny. Chemopreventive agents can influence this balance in such a way that favoring apoptosis in cancer cells is the outcome. Among these, chemopreventive agents can induce reduction of mitochondrial membrane potential, which is an essential process initiated in intrinsic apoptosis. This disruption results to the release of other apoptogenic factors such as cytochrome c, Smac/DIABLO and AIF into the cytosol from the mitochondria.⁶³ These chemopreventive agents can suppress anti-apoptotic proteins (Bcl-2, Bcl-xL) and upregulate levels of pro-apoptotic proteins (Bax, Bak) that lead to MOMP and apoptosis. For example, it has been found that EGCG lowers the expression of Bcl-2 proteins and at the same time raises Bax proteins resulting into apoptosis. For further activation, cytochrome c moving into the cytoplasm interacts with Apaf-1 which results in the formation of apoptosome and activation of caspase-9. Some other proteins localized to the mitochondria include Smac/DIABLO, which can inactivate IAPs (inhibitor of apoptosis proteins) that, in turn, down regulates caspase activity as well as encouraging apoptosis.⁶⁴

Therefore, many chemopreventive agents by modulating the rate of mitochondrial function and alteration of the ratio of the pro- apoptotic proteins and anti-apoptotic one desires directed apoptosis in cancer cells leaving normal cells intact. In fact, these sorts of selective induction of apoptosis are vital for the cancer prevention as well as cancer treatment since they destroy mutated cells without affecting the normal cells.⁶⁵

Inhibition of Angiogenesis and Metastasis

Angiogenesis is an essential event during tumor growth and metastasis to receive an adequate blood circulation concerning oxygen and nutrients needed for the growth and proliferating cells. Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis that stimulate the endothelial cell proliferation and enhance the migration and formation of blood vessels.⁶⁶ C. sinensis BACs inhibit angiogenesis by suppressing VEGF production or activity.⁶⁷ Tea BACs inhibit the expression of VEGF at the transcriptional level in multiple cancer cell lines by down regulating Protumorigenic hypoxia-inducible factor-1α (HIF-1α), a common condition in most solid tumors.⁶⁸ VEGF works through interacting with VEGF receptors (VEGFRs) on the surface of endothelial cells, and tea BACs block the interaction between the both to inhibit angiogenesis.⁶⁸  Tea BACs can also interact within other pathways (PI3K/Akt pathway), activate VEGF, which are useful for regulating angiogenesis.⁶⁹ This inhibition can slow down tumor growth and reduce the potential for metastasis (Figure 2).

Figure 2: BACs in tea contribute to chemoprevention through various mechanisms of action (Antioxidant/Prooxidant, Angiogenesis, Proliferation and Migration). Click here to view Figure

MMP Inhibition

Matrix metalloproteinases (MMPs) are enzymes capable of breaking down large amounts of the extracellular matrix (ECM). This process is very significant in the invasion of the cancer cells and formation of new tissue or metastases because it enables the cancer cell to cross the ECM front that had been formed and to proliferate into the neighboring tissues. MMPs, particularly MMP-2 and MMP-9 that are often overexpressed on the tumors and can be detected when metastatic potential and poor prognosis are increased.⁷⁰ Various chemopreventive agents reported in tea plant can affect the expression of MMPs,⁷¹ and its activity and expression through multiple mechanisms. Among the above-discussed chemopreventive additives some influence the MMPs enzymatic activity right at the molecular level. For instance, EGCG has been shown to bind and fix the MMPs active site and block any further degradation of ECM.⁷¹ This direct inhibition may assist in prevention of cancer cells to invade and migrating to the rest of the body.

Tea bioactive molecules also suppress MMP at the transcript levels in cancer cells also.⁷² It can also inhibit other transcription factors for instance AP-1 and NF-κB that are activators of MMP genes.⁷² They prevent the production of MMP, reducing the overall proteolytic activity in the area surrounding the neoplastic cell proliferation and compromising the cancer cells invasion capabilities. C. sinensis chemoprevention compounds target signaling pathways which regulate expression of MMPs.⁷² For example, they can inhibit the MAPK and PI3K/Akt pathways by which MMPs are produced in reaction to signals.⁷³ Such agents assist in altering these pathways that subsequently reduces MMP generation and activity besides the capacity of the cancer cells to invade the surrounding ECM. By inhibiting MMP activity and expression, chemopreventive agents can significantly reduce cancer cell invasion and metastasis. This inhibition helps to contain the tumor within its original site, preventing the spread of cancer to distant organs and improving overall prognosis.⁷⁴ 

Preclinical Studies and in vivo/in vitro evidences

PC xenograft models involve implanting human PC cells into immunocompromised mice, allowing researchers to study tumor growth and the effects of potential chemopreventive agents in a living organism. These models offer worthy information concerning the efficiency of diverse compounds as anti-tumor agents.⁷⁵ Several of these studies have shown that TP and especially EGCG effectively suppress the proliferation of PC xenografts. For instance, one investigation revealed that the effects of green tea polyphenols significantly inhibited the growth of human prostate carcinoma xenografts in nude mice. The treated group had smaller tumor size and had diminished angiogenesis related-proteins like VEGF to the untreated group (Figure 3). Another study investigated the effects of green tea polyphenols on the growth of androgen-dependent as well as androgen-independent PC xenografts. The outcomes revealed that green tea polyphenols were able to have an effect on both type of tumors and therefore, showed that green tea polyphenols could be more effective in acting as a chemopreventive agent.

Figure 3: The effects of tea compounds on PC, including in vitro, in vivo, and clinical studies. Click here to view Figure

Dose-response studies are critical for understanding the effective concentrations of chemo preventive agents and their potential toxicity. These studies aid in the identification of the greatest amount for drug effectiveness while at the same time excluding any unfavorable side effects. Research on the dose-response relationships of tea polyphenols has shown that higher doses generally result in greater tumor inhibition. However, there is a threshold beyond which no additional benefits are observed, and higher doses may even lead to toxicity. For example, a study evaluated different doses of green tea polyphenols in mice with PC xenografts. However, the research established that moderate doses exhibit considerable suppression tumor growth, very high doses did not provide additional benefits and were associated with liver toxicity.

Specifically, the in vitro experiments using the PC cell lines allow the investigation of the cellular basis of chemopreventive agents. These studies allow researchers to dissect the specific pathways and targets affected by these compounds. Numerous studies investigated the consequence of tea polyphenols on different PC cells including LNCaP, PC-3 and DU145. For example, it has been discovered that cellular studies indicate that EGCG reduces the proliferation effect on these cell lines and that it triggers apoptosis. EGCG has been found to decrease the viability of PC cells in a dose-dependent manner by modulating cell cycle regulators, such as p21 and p27, and inducing cell cycle arrest at the G1 phase.^76-77 Additionally, EGCG has been demonstrated to cause apoptosis in the prostate-cancer cells by both the intrinsic and extrinsic systems. The compound has effect on the caspase-3 and caspase-9 which in turn causes DNA fragmentation and apoptotic cell death. In addition to this, EGCG has been observed to suppress Bcl-2, which is an anti-apoptotic protein and at the same increase Bax, which is a pro apoptotic protein thus enhancing the mitochondrial mediated apoptosis.⁷⁸ 

Molecular Targets and Pathways

Chemopreventive agents work through changing the events within selected molecular targets that regulate the process of carcinogenesis.⁷⁹ Tea polyphenols modulate several molecular targets in PC including NF-κB, AMPK, and PI3K/Akt pathways are noteworthy.^80-81 NF-κB regulates genes involved in inflammation, cell proliferation, and survival. EGCG has been shown to inhibit the activation of NF-κB in PC cells, thereby reducing the expression of pro-inflammatory cytokines and anti-apoptotic proteins.⁸² Energy sensor AMPK regulates cellular metabolism and growth, while tea polyphenols activated AMPK inhibit mTOR signaling, downregulate translational activity, and cell proliferation in PC cells.⁸³ Moreover, EGCG has been shown to inhibit PI3K activity and reduce Akt phosphorylation, leading to decreased cell survival by inducing apoptosis in PC cells.⁶⁹ Tea polyphenols can disrupt the molecular mechanisms driving PC progression, highlighting their potential as effective chemopreventive agents. 

Clinical studies and human evidence

Population-based epidemiological studies explored the link between drinking tea and the occurrence of PC and offers valuable insights into how tea might protect against PC by examining the dietary habits, lifestyles, and cancer rates. It is found that men who regularly drink tea tend to have a lower risk of developing PC.⁸⁴ This study highlighted the potential protective effects of the green tea for advanced PC. Certain meta-analysis comprising of 24 observational studies covering 155,000 participants indicated that increased consumption of green tea helps lower the risk of developing PC especially among Asian men. No significant effects of tea were observed on dyslipidemia and there were no consistent findings concerning black tea and other kinds of tea, evidencing that further research is required to establish the effects of other tea sorts. Correlation studies find a relation between frequent tea intake with amount consumed, and the occurrence of PC. Some of these control factors include age, family history, smoking and other dietary measures to isolate the effects of tea consumption. These studies often use randomized controlled trials (RCTs) which are applied to compare the effects in the groups consuming tea interventional agents and the control groups which may be given only placebo or standard treatment.⁸⁴ The clinical trial of different teas and their outcomes are discussed in table 2.

A double-blind placebo-controlled clinical trial study assessed green tea catechins exposed to PC patients showed a lower PSA than placebo group.⁸⁵ Decrease in PSA is linked with progression of PC, may indicate possible use of green tea catechins in controlling PC. Clinical trials have reported multifarious outcomes regarding the effects of tea on PC biomarkers and progression.⁸⁶ The results can vary due to different type of teas studied, the duration of intervention, and the specific endpoints assessed (PSA levels, tumor progression). In a systematic review and meta-analysis, which included 17 studies on over a million participants, green tea consumption was associated with a reduced risk of PC.⁸⁷ Clinical trials on tea and PC can encounter some limitations, another concern is the studies heterogeneity involving study design and methodology that may influence the findings comparability and assessment across the trials. Variations in tea composition, dose, and bioavailability also contribute to inconsistencies in finding. Adherence to tea interventions and the accurate assessment of tea consumption through self-reported methods can also introduce bias into study outcomes. Variations in genetic susceptibility, dietary patterns, and lifestyle factors among populations can influence the observed effects of tea on PC outcomes.⁸⁸ 

Table 2: Summary of Clinical Trials Investigating the Effects of Tea Consumption on PC Risk.

Bioavailability and Metabolism of Tea Compounds

The level of tea polyphenols which is available in the body depends on the kind of tea used, how it was prepared and the digestive process of an individual. Tea polyphenols deep tissue distribution is also affected by their metabolism that occurs after they undergo intense gastrointestinal tract and liver metabolism once ingested.⁹⁸

Epidemiological studies demonstrated that antioxidant present in tea leaves, tea polyphenols are conjugated in the liver and are then excreted.⁹⁹ These compounds can enhance the bioavailability when taken in presence of food matrix, the type of gut microbiota and genetic differences in enzyme-metabolizing systems. The approaches to increase bioavailability of the tea compounds are increasing the solubility by applying formulation approaches, concomitant use of bioavailability enhancers such as Piperine, and by using nano-particular formulations for cellular uptake.¹⁰⁰ 

Conclusion

BACs obtained from tea (C. sinensis) are a potential source for the chemoprevention of PC. Existence of compounds as catechins (EGCG), flavonoids (quercetin, kaempferol), alkaloids (caffeine, theobromine), theanine, vitamins, minerals, and volatile oils have antioxidant, anti-inflammatory, and possibly anticancer effects. These BACs have been proved to exhibit antiproliferative, antiaromatase, and antioxidant potentials in altering the various signaling pathways associated with PC. Furthermore, the synergistic interactions among these BACs enhance their overall therapeutic potential, offering a holistic approach to reducing the risk of PC. While challenges remain in translating these findings into clinical applications, ongoing research and clinical trials continue to support the promising role of tea-derived BACs in PC chemoprevention. With the advancement in understanding molecular mechanisms of action and optimized targeted delivery and efficacy, tea BACs stand poised to contribute significantly to strategies aimed at preventing and managing PC.

Acknowledgement

The author would like to thank China Tea Science Society.

Funding Sources

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Conflict of Interest

The authors do not have any conflict of interest.

Data Availability Statement

Even though adequate data has been given in the form of tables and figures, however, all authors declare that if more data required then the data will be provided on request basis.

Ethical Statement

This research did not involve human participants, animal subjects, or any material that requires ethical approval

Informed Consent Statement

This study did not involve human participants, and therefore, informed consent was not required.

Permission to Reproduce Material from Other Sources

Not applicable

Clinical Trial Registration

This research does not involve any clinical trials.

Author Contributions

• Mingxi Li – Proposed this idea and drafted initial manuscript, Helped in preparing figures and tables and overall quality of the manuscript.
• Muhammad Farrukh Nisar – Proposed this idea and drafted initial manuscript, Helped in preparing figures and tables and overall quality of the manuscript.
• Yudi Gan – Helped in preparing figures and tables and overall quality of the manuscript.
• Chunpeng Wan – Proposed this idea and drafted initial manuscript, Helped in preparing figures and tables and overall quality of the manuscript.  

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Abbreviations

AMPK – AMP-Activated Protein Kinase

Apaf-1 – Apoptotic Protease Activating Factor-1

BACs – Bioactive compounds

DISC – Death-Inducing Signaling Complex

DNA – Deoxyribonucleic acid

EC – Epicatechin

ECG – EpicatechinGallate

ECM – Extracellular Matrix

EGC – Epigallocatechin

EGCG – EpigallocatechinGallate

MMPs – Matrix Metalloproteinases

PC – Prostate Cancer

ROS – Reactive Oxygen Species

SOD – Superoxide Dismutase

VEGF – Vascular Endothelial Growth Factor